Doxorubicin has been used for a long time in the antineoplastic treatment, for a review see Arcamone, ed. "Doxorubicin", Acad. Press, New York 1981. A serious side-effect of doxorubicin is the onset of often irreversible myocardiopathies.
Epirubicin was found to have advantageous pharmacological properties compared with its analogue, showing an equivalent antitumoral activity but less side-effects (R. B. Weiss et al., Cancer Chemother. Pharmacol. 18, 185-97 (1986)).
The starting synthesis of epirubicin involved the condensation between daunorubicin aglycone of formula (B) ##STR2## and the 1-chloro-derivative of acosamine protected as trifluoroacetamide (Arcamone, F. et al., J. Med. Chem., 18, 7, 703-707, (1975)), subsequent deprotection and working up of the side chain with a method well known in literature, already used for the transformation of daunorubicin into doxorubicin (E. M. Acton, J. Med. Chem., 17,65 (1974); DE 1917874).
Trifluoroacetylacosaminyl chloride N,O derivative was obtained by synthetic transformation of various natural sugars with a number of rather complex, expensive processes.
Italian Patent 1,163,001 and, subsequently, G. Bonadonna in "Advances in Anthracycline Chemotherapy Epirubicin", Masson Ed., Milan, Italy, 1984, disclose a synthesis process carried out on the whole N-trifluoroacetyldaunorubicin glycoside. This process comprises the oxidation of the hydroxy group at C-4' to keto group, then its stereoselective reduction to hydroxy group by means of sodium borohydride. The oxidation reaction has to be performed at exceedingly low temperatures (-70.degree. C.). The keto derivative is very delicate and unstable. Moreover, the reduction with sodium borohydride must be carried out at a low temperature to minimize the competitive reduction of the aglycone carbonyl group. Although not stated, the maximum isomerization yields which can deduced from said patent are of about 48%.
Another method for the epimerization of C-4' is described by B. Barbieri et al. Cancer Research, 47, 4001 (1987). This method aims at obtaining 4'-halogen-daunorubicin, then effects the epimerization from the equatorial configuration to the axial one, i.e. in a direction opposite to that desired in the present invention. The epimerization reaction is carried out by nucleophilic substitution of the triflate group (equatorial) with a tetrabutylammonium halide.